PIK3CA-related overgrowth spectrum (PROS) encompasses a set of rare disorders caused by pathogenic variants in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Under normal circumstances, this pathway is activated by the stimulation of tyrosine kinase receptors that leads to tightly regulated cell growth, proliferation, and migration. However, in PROS, pathogenic variants in the PI3KCA gene lead to an abnormal accumulation of the enzyme at the cell membrane, resulting in persistent activation of the PI3K/AKT/mTOR pathway and dysregulated cell overgrowth.
Excessive cell growth and proliferation leads to the overgrowth of tissues and organs characteristically seen in PROS. Because PIK3CA pathogenic variants are not present in every cell, only certain areas of the body are affected by overgrowth; these can range from isolated digits to whole limbs, the trunk, or one or more tissues or organs.
The diagnosis of PROS is typically confirmed through genetic testing of the PIK3CA gene, which can identify the specific pathogenic variants responsible for the disorder.
Here are five things to know about PROS.
1. PROS comprises a heterogeneous group of rare congenital diseases.
PROS is a term used to describe a group of rare congenital disorders that are characterized by abnormal, segmental, or lateralized growth of various body tissues and regions. These disorders are linked by a common cause: mosaic pathogenic gain-of-function variants in the PIK3CA gene. The genetic pathogenic variants that cause these disorders are not passed down from parent to child but instead result from changes to genes during embryonic development.
PROS encompasses a range of clinical entities, each with its own set of characteristics but sharing phenotypic similarities. These clinical entities include:
- Fibroadipose hyperplasia (also called fibroadipose overgrowth)
- CLOVES syndrome (congenital lipomatosis overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal or spinal abnormalities)
- Klippel-Trenaunay syndrome
- Megalencephaly-capillary malformation (MCAP) syndrome
- Hemihyperplasia‐multiple lipomatosis syndrome
- Dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia
- Facial infiltrating lipomatosis (a congenital disorder that causes overgrowth of one side of the face)
- Macrodactyly
- Isolated tissue dysplasia-overgrowth phenotypes: lymphatic malformations, vascular malformations, venous malformations, lipomatosis
- CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth)
The global epidemiologic characteristics of PROS are not well documented, but it is estimated that each of these conditions individually has a prevalence rate of fewer than 1 case per million population, and the collective prevalence of PROS-related syndromes is 14 cases per million population. Owing to its low prevalence and the variety of diseases it encompasses, PROS is classified as a rare disease.
2. PROS diseases have specific phenotypic features with common characteristics that result in overlapping phenomena.
The severity of clinical presentation varies in patients with PROS; some have tissue-specific distribution whereas others are more pleiotropic. In general, this condition is marked by segmental overgrowth of multiple tissues, including:
- Organs and other tissues: Excessive and asymmetric overgrowth can affect the skin, bones, muscles, and other structures, leading to disfigurement and functional impairments. The overgrowth typically follows a distal to proximal pattern, mostly unilateral and affecting the lower limbs.
- Brain: Enlargement of specific structures, including ventriculomegaly, a thick corpus callosum, or cerebellar tonsillar ectopia, can cause megalencephaly, which can lead to developmental delay, seizures, cortical dysplasia, and/or hydrocephalus.
- Vasculature: Capillary, venous, arteriovenous, and lymphatic malformations are common and occur in about 43% of patients. These abnormalities can contribute to additional complications, including swelling, pain, and increased risk for bleeding.
- Skin: Thickened epidermal nevi and pigmentary anomalies, such as hyperpigmentation or hypopigmentation, are common. These skin manifestations can be early signs of PROS and may aid in diagnosis.
- Skeletal system: Anomalies can include polydactyly, macrodactyly, macrodontia, and scoliosis or other spinal abnormalities.
- Lipomatosis overgrowth: This can occur with or without regional reduction of adipose tissue on the trunk and limbs.
- Lymphatic system: Isolated malformations may include dilated vascular channels lined by lymphatic endothelial cells, which may lead to fluid-filled cysts that usually grow proportionally with the growth of the affected person and may cause pain or significant morbidity if they are infiltrative.